Hepatoblastoma

Published Categorized as Gastrointestinal (GI) System, ORGAN SYSTEMS
Micrograph showing a hepatoblastoma (right of image) and normal liver (left of image). H&E stain. | Nephron - CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=14887713

Hepatoblastoma (HB) is the most common primary hepatic tumor of childhood originating from primitive hepatic stem cells.

  • M/C primary malignant liver tumor in pediatric patients (most often within the first 2 years of life)
  • The histologic types are subdivided into the epithelial type and the mixed type.

History:

In 1898, the first case of a child with hepatoblastoma (HB) was published: A 6-week-old boy whose autopsy showed a large tumor that occupied the lower half of the right liver lobe. Because cysts and cartilaginous and bony deposits were seen, the tumor was described as a teratoma, with tissue representatives of the three embryonic germ cell layers. In 1962, the term “Hepatoblastoma” was introduced for this type of tumor by Willis, who defined it as “an embryonic tumor that contains hepatic epithelial parenchyma.” At that time, HB was usually not distinguished from hepatocellular carcinoma (HCC). Through the work of Ishak and Glunz in 1967, morphologic criteria were defined for HB and HCC that were refined in the decades that followed. HB is currently thought to originate from the hepatoblast (hepatocyte precursor cell) that often recapitulates the stages of liver development, displaying a combination of histological patterns.


Etiology

Risk factors:

  • Fetal risk factors: Low birth weight infants
  • Pregnancy risk factors: Preeclampsia and parental tobacco smoking before and during pregnancy
  • Other factors: Oxygen therapy, certain medication (furosemide), radiation, plasticizers, and total parenteral nutrition (TPN)

Disease associations:

Most tumors are sporadic, but one-third of cases are associated with other conditions
  • Beckwith-Weidemann
  • Familial adenomatous polyposis (FAP)
  • Edward syndrome (trisomy 18)
  • Nephroblastoma
  • Down syndrome

Pathology

International Consensus Classification:

Hepatoblastomas originate from primitive hepatic stem cells that give rise to the epithelial components of the liver. Classically, these tumors are divided into 2 broad categories: epithelial type (E-HB) and mixed epithelial and mesenchymal type (MEM-HB).
International consensus classification of the histological subtypes of hepatoblastoma | Aronson, D. C., Czauderna, P., Maibach, R., Perilongo, G., & Morland, B. (2014). The treatment of hepatoblastoma: Its evolution and the current status as per the SIOPEL trials. Journal of Indian Association of Pediatric Surgeons, 19(4), 201–207. https://doi.org/10.4103/0971-9261.142001

Epithelial type (E-HB) hepatoblastoma:

Includes fetal, pleomorphic, embryonal, macrotrabecular, small cell undifferentiated (SCU), cholangioblastic and mixed epithelial variants.
  • Fetal subtype: Further stratified into 4 categories: well-differentiated; crowded or mitotically active; pleomorphic, poorly differentiated; and anaplastic.
  • Embryonal subtype (M/C subtype): Consists of basophilic cells with scant cytoplasm and increased mitotic rate that is arranged in nests, trabeculae, acini, pseudorosettes, or sheets
  • Macrotrabecular subtype: Arranged in trabeculae that are more than ten cells thick
  • Small cell undifferentiated (SCU) subtype: Consists of dyscohesive, uniform round cells arranged in sheets with increased mitotic activity.
  • Cholangioblastic variant: Has bile ducts, typically located at the periphery of epithelial sheets.

Mixed epithelial and mesenchymal type (MEM-HB):

Comprises 20-30% of tumors and contains a variable combination of epithelial and mesenchymal components. Most commonly, the epithelial component is fetal or embryonal, and the mesenchymal component is osteoid.
  • Stromal derivatives: Spindle cells, osteoid, skeletal muscle, and cartilage
  • Teratoid derivatives: Primitive endoderm, neural derivatives, melanin, squamous and glandular elements
Histological subtypes of human HB. (A) Pure fetal HB showing the organization in trabeculae of the tumor. Tumor cells resemble fetal hepatocytes and show a large cytoplasm, which appears either clear/white or pink due to the different content of glycogen and lipids of the tumor cells. This peculiar “light and dark pattern” is better appreciable at higher magnification in (B); (C) mixed fetal-embryonal HB, characterized by the presence of two distinct population of cells. While fetal tumor cells (*) display a pink and large cytoplasm, embryonal HB cells (arrows) show prominent, highly basophilic nuclei, a small cytoplasm, and a high nuclear/cytoplasmic ratio; (D) often, embryonal-like HB cells tend to form rosettes (“pseudo-rosettes”), acini or tubules, exhibiting a pseudoglandular phenotype; (E) examples of a SCU HB. SCU cells have minimal cytoplasm and round lightly chromatic nuclei. Different from embryonal-like cells, SCU cells do not form tubules, pseudo-glands or any other organized structure; (F) part of a mixed epithelial-mesenchymal HB containing osteoid as a mesenchymal component. Original magnification: 100× in C; 200× in A; 400× in B, D, E, and F. Hematoxylin and eosin staining was employed. HB, hepatoblastoma; SCU, small cell undifferentiated. | Calvisi, D. F., & Solinas, A. (2020). Hepatoblastoma: current knowledge and promises from preclinical studies. Translational gastroenterology and hepatology, 5, 42. https://doi.org/10.21037/tgh.2019.12.03

Clinical presentation

Hepatoblastomas usually present with as a single, mildly painful, rapidly enlarging abdominal mass that arises in the right lobe of the liver in 55% to 60% of cases Rapid enlargement of these tumors rarely results in tumor rupture and hemorrhage. Tumors may reach up to 25 cm in size. Most tumors are solitary; however, up to 15% of tumors are multifocal.

Some cases are associated with non-specific symptoms such as weight loss, failure to thrive or anorexia. Significant elevations of alpha-fetoprotein (AFP) are observed in 90% of patients, and rarely, a paraneoplastic syndrome can occur.

Metastasis:

The lung is the most common metastatic site for hepatoblastoma and approximately 20% of the initially diagnosed hepatoblastoma cases have also presented with lung metastasis. The initial treatment for hepatoblastoma with lung metastasis is neoadjuvant chemotherapy.
Indocyanine green (ICG) guided thoracoscopic surgery. Green color indicates lung metastasis. | Yang, T., Whitlock, R. S., & Vasudevan, S. A. (2019). Surgical Management of Hepatoblastoma and Recent Advances. Cancers, 11(12), 1944. https://doi.org/10.3390/cancers11121944

Diagnosis

Ultrasound (US) and either computed tomography (CT) or magnetic resonance imaging (MRI) are the imaging modalities used to define the extent of tumor involvement of the liver and aid in pre-surgical planning. A chest CT can help detect lung metastasis; the lung is the most common location of metastases and up to 20% of cases present with metastases.[7] After imaging, a biopsy, alpha-fetoprotein level, liver function tests, and a hepatitis panel are performed as needed. Consent for participation in biologic studies should be requested before the biopsy is performed so the specimen can be properly allocated and handled.

Pre-Treatment Extent of tumor (PRETEXT):

The pre-treatment extent of tumor (PRETEXT) system was developed by SIOPEL to standardize imaging evaluation and risk stratification for hepatoblastoma prior to neoadjuvant chemotherapy, whereas the POST-TEXT (post-treatment extent of disease) system uses the same standards as PRETEXT but classifies hepatoblastoma during neoadjuvant chemotherapy
  • PRETEXT annotation factor is determined to be positive if at least 1 of the following 5 factors are present:
    • Involvement of the vena cava or all 3 hepatic veins, or both (V)
    • Involvement of portal bifurcation or both right and left portal veins, or both (P)
    • Extrahepatic contiguous tumor extension (E)
    • Multifocal liver tumor (F)
    • Tumor rupture at diagnosis (R)
PRETEXT, anatomic extent of tumor to define resectability. Referred to as POST-TEXT after chemotherapy. | Dr Zezo. (2021) Liver Tumors. Retrieved October 22, 2021, from https://oncohemakey.com/liver-tumors/

Differential Diagnosis

  • Hepatocellular carcinoma (HCC): Similar to macrotrabecular subtype; however it usually adults with risk factors such as metabolic disorders, liver cirrhosis, or childhood hepatitis B infection
  • Focal nodular hyperplasia: Usually affects older children and adults
  • Hepatic adenoma: Resemble pure fetal hepatoblastomas; however, these rarely occur under 5 years of age unless they have an underlying metabolic disorder.
  • Lymphoma
  • Metastases

Management

Surgical resection:

Mainstay of treatment with resectability of the tumor determining the need for neo-adjuvant or adjuvant chemotherapy. The five-year overall survival rate for hepatoblastoma is approximately 80% with those who underwent partial hepatectomy achieving survival rates as high as 91%
Resection at diagnosis of pure fetal HB. Untreated without prior chemotherapy exposure. | Dr Zezo. (2021) Liver Tumors. Retrieved October 22, 2021, from https://oncohemakey.com/liver-tumors/

Chemotherapy:

Neoadjuvant chemotherapy is now the standard of care for most cases. Neoadjuvant chemotherapy and surgical resection produce a cure rate of approximately 70%
  • Platinum-based chemotherapy regimens
Mixed HB. Postchemotherapy specimen with abundant necrosis and osteoid. | Dr Zezo. (2021) Liver Tumors. Retrieved October 22, 2021, from https://oncohemakey.com/liver-tumors/

Liver transplant:

If liver is unresectable and chemotherapy fails to shrink the tumor to a resectable size, a liver transplant can be done and has a good long-term survival rate. At presentation, approximately 60% of tumors are unresectable.

Prognosis:

Prognosis is based on numerous factors including age of diagnosis, PRETEXT group, metastases, alfa fetal protein (AFP) levels, histologic subtype, completeness of resection, and clinical stage of the disease.

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